[摘要] 目的:探討定量磁化率成像(QSM)技術(shù)對(duì)新生兒高膽紅素血癥(NHB)潛在腦損傷的預(yù)測(cè)價(jià)值。方法:對(duì)33例足月NHB患兒(NHB組)和12例足月健康新生兒(對(duì)照組)行MRI掃描,經(jīng)后處理得到腦深部灰質(zhì)核團(tuán)的磁化率值。比較2組磁化率值差異,分析評(píng)估各腦區(qū)磁化率值與血清總膽紅素濃度之間的相關(guān)性及QSM技術(shù)對(duì)NHB的預(yù)測(cè)效能。結(jié)果:NHB組腦深部灰質(zhì)核團(tuán)的磁化率值較對(duì)照組高,但僅殼核差異有統(tǒng)計(jì)學(xué)意義(t=-3.561,P=0.001);對(duì)照組血清總膽紅素濃度與蒼白球的磁化率值呈正相關(guān)(r=0.769,P=0.043),NHB組血清總膽紅素濃度與右側(cè)尾狀核的磁化率值呈負(fù)相關(guān)(r=-0.447,P=0.009)。Apgar評(píng)分和血清總膽紅素濃度可同時(shí)影響NHB組右側(cè)尾狀核的磁化率值;在腦深部灰質(zhì)核團(tuán)中,殼核磁化率值對(duì)NHB的預(yù)測(cè)效能最佳(AUC=0.780)。結(jié)論:QSM技術(shù)能無(wú)創(chuàng)、靈敏、高效地反映NHB患兒潛在的腦損傷,為該病的防治提供新思路和干預(yù)靶點(diǎn)。
[關(guān)鍵詞] 磁共振成像;磁化率成像;嬰兒,新生;高膽紅素血癥;腦深部灰質(zhì)核團(tuán)
Value of quantitative susceptibility mapping technology in predicting potential brain injury in neonatal hyperbilirubinemia
WANG Yuanyuan1,YANG Linfeng2,CHEN Tao2,GUO Lingfei1,3
1School of Medical Imaging,Binzhou Medical University,Yantai 264003,China;2Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University,Jinan 250001,China;3Department of Radiology,Shandong Provincial Hospital Affiliated to Shandong First Medical University,Jinan 250021,China.
[Abstract] Objective:To investigate the value of quantitative susceptibility mapping (QSM) technology in predicting the potential brain injury in patients with neonatal hyperbilirubinemia (NHB). Methods:33 full-term neonates with NHB (NHB group) and 12 full-term healthy neonates (control group) underwent MRI scans. The susceptibility values of the deep gray matter nuclei were obtained after post-processing and compared between the two groups. The correlation between the susceptibility values of each brain region and serum total bilirubin (TBil) concentration was analyzed. The ability of QSM technology in the diagnosis of NHB was evaluated. Results:The susceptibility values of the deep gray matter nucleus in NHB group were higher than those in the control group,especially of the putamen (t=-3.561,P=0.001). The TBil concentration was positively correlated with the susceptibility values of globus pallidus in the control group (r=0.769,P=0.043),while the TBil concentration was negatively correlated with the susceptibility values of right caudate nucleus in the NHB group (r=-0.447,P=0.009). Apgar score and TBil concentration concurrently affected the susceptibility values of the right caudate nucleus in NHB group. Among the above brain regions,the susceptibility value of putamen had the best efficiency in diagnosing NHB,with an AUC of 0.780. Conclusions:QSM technology can noninvasively,sensitively and efficiently reflect the potential brain damage in NHB,and provide new ideas and intervention targets for the prevention and treatment of NHB.
[Key words] Magnetic resonance imaging;Quantitative susceptibility mapping;Infant,newborn;Hyperbilirubinemia;Deep gray matter nuclei
新生兒高膽紅素血癥(neonatal hyperbilirubinemia,NHB)是新生兒常見的膽紅素異常代謝疾病,以血液循環(huán)中血清膽紅素升高為特征,伴皮膚、黏膜和鞏膜黃染等典型臨床表現(xiàn)[1]。最新研究顯示,足月新生兒中NHB發(fā)病率為16.6%,全球每10萬(wàn)名新生兒中就有2.4例出現(xiàn)膽紅素神經(jīng)毒性癥狀[2],若不及時(shí)有效治療,膽紅素神經(jīng)毒性可誘發(fā)急慢性膽紅素腦病、核黃疸譜系障礙,甚至死亡[3]。目前,NHB的診斷主要依賴實(shí)驗(yàn)室血清膽紅素濃度檢測(cè)[4],但無(wú)法明確患兒腦損傷情況。MRI可無(wú)創(chuàng)檢測(cè)NHB患兒腦損傷,在最常受累的腦深部灰質(zhì)核團(tuán)中急性腦損傷呈T1WI高信號(hào),慢性腦損傷呈T2WI高信號(hào)[5]。由于腦深部灰質(zhì)核團(tuán)中存在鞘磷脂,因此MRI結(jié)構(gòu)像掃描結(jié)果假陽(yáng)性概率較高[6]。定量磁化率成像(quantitative susceptibility mapping,QSM)是一種測(cè)量組織磁化率的MRI技術(shù),可無(wú)創(chuàng)分析腦鐵含量,且一致性和重復(fù)性良好[7]。因此,本研究探討QSM技術(shù)對(duì)NHB患兒腦損傷的預(yù)測(cè)價(jià)值。
1" 資料與方法
1.1" 一般資料
收集2019年5月至2022年9月在山東第一醫(yī)科大學(xué)附屬濟(jì)南婦幼保健院就診的NHB患兒資料。納入標(biāo)準(zhǔn):①足月圍產(chǎn)期新生兒;②正常出生體質(zhì)量;③符合NHB診斷標(biāo)準(zhǔn),血清總膽紅素濃度gt;220 μmol/L。排除標(biāo)準(zhǔn):①溶血性疾?。òˋBO、Rh溶血等);②急慢性膽紅素腦??;③MRI檢查陽(yáng)性、先天性神經(jīng)系統(tǒng)發(fā)育異?;蛏窠?jīng)系統(tǒng)疾病;④中樞神經(jīng)系統(tǒng)陽(yáng)性體征;⑤MRI偽影嚴(yán)重、影響觀察和測(cè)量。共納入33例NHB患兒(NHB組),同期收集12例健康新生兒作為對(duì)照組。本研究經(jīng)山東第一醫(yī)科大學(xué)附屬濟(jì)南婦幼保健院倫理委員會(huì)審批通過(guò)(倫理號(hào):2019-1-002)。
1.2" 儀器與方法
2組均行MRI掃描。采用Philips 1.5 T MRI掃描儀和16通道相控陣頭線圈。檢查前30 min給予10%水合氯醛灌腸,劑量30~40 mg/kg體質(zhì)量?;純喝⊙雠P位,睡眠狀態(tài)下使用軟墊固定頭部。掃描序列:①解剖結(jié)構(gòu)像,3D T1WI序列,TR 25 ms,TE 6.1 ms,TI 900 ms,翻轉(zhuǎn)角30°,體素1 mm×1 mm×1 mm;②用于QSM分析的三維多回波梯度回波(ME-GRE)序列,TR 50 ms,TE 5 ms,TE 9 ms,回波數(shù)5,翻轉(zhuǎn)角20°,體素1 mm×1 mm×3 mm。③行T2WI和T2FLAIR序列掃描以排除腦內(nèi)異常。
采用自動(dòng)均勻腦脊液零參考算法(MEDI+0)行形態(tài)學(xué)偶極子反轉(zhuǎn),從多梯度回波(mGRE)圖像數(shù)據(jù)中獲得QSM圖[4-5]。步驟:①對(duì)多回波數(shù)據(jù)行非線性擬合計(jì)算總場(chǎng)[6];②利用投影到偶極子場(chǎng)算法展開空間場(chǎng)、去除背景場(chǎng)及計(jì)算局部場(chǎng)[7];③行反演計(jì)算得到最終的QSM圖。采用ITK-SNAP v3.8軟件(www.itksnap.org),由放射科醫(yī)師在QSM圖上手動(dòng)勾畫并填充深部灰質(zhì)核團(tuán)(包括殼核、蒼白球、尾狀核)(圖1),提取并記錄各腦區(qū)的平均磁化率值。
1.3" 統(tǒng)計(jì)學(xué)方法
采用SPSS 25.0軟件進(jìn)行數(shù)據(jù)分析。符合正態(tài)分布的計(jì)量資料以x±s表示,組間比較行兩獨(dú)立樣本t檢驗(yàn)或秩和檢驗(yàn)。計(jì)數(shù)資料以例(%)表示,組間比較行[χ]2檢驗(yàn)。比較2組臨床資料及各腦區(qū)磁化率值的差異。各腦區(qū)磁化率值與臨床指標(biāo)之間的相關(guān)性采用Pearson和Spearman雙變量相關(guān)性分析。采用多元線性回歸分析確定各腦區(qū)磁化率值的影響因素。采用ROC曲線評(píng)估各腦區(qū)磁化率值對(duì)NHB的診斷效能。各腦區(qū)磁化率值預(yù)測(cè)NHB的AUC的比較行DoLong檢驗(yàn)。以Plt;0.05為差異有統(tǒng)計(jì)學(xué)意義。
2" 結(jié)果
2.1" 2組臨床資料比較(表1)
2組性別、孕周、MRI檢查時(shí)出生天數(shù)、生育史、臍帶繞頸、胎膜早破、純母乳喂養(yǎng)、自然分娩等差異均無(wú)統(tǒng)計(jì)學(xué)意義(均P>0.05);出生體質(zhì)量、Apgar評(píng)分、血清總膽紅素濃度、羊水污染、宮內(nèi)窘迫等差異均有統(tǒng)計(jì)學(xué)意義(均Plt;0.05)。
2.2" 2組深部灰質(zhì)核團(tuán)的磁化率值比較(表2,3)
NHB組殼核、蒼白球、尾狀核的磁化率值均高于對(duì)照組,但僅殼核的磁化率值差異有統(tǒng)計(jì)學(xué)意義(t=-3.561,P=0.001)。2組組內(nèi)各腦區(qū)左右兩側(cè)磁化率值差異均無(wú)統(tǒng)計(jì)學(xué)意義(均Pgt;0.05)。
2.3" 各腦區(qū)磁化率值與血清總膽紅素濃度之間的相關(guān)性分析
對(duì)照組血清總膽紅素濃度與蒼白球的磁化率值呈正相關(guān)(r=0.769,P=0.043),NHB組血清總膽紅素濃度與右側(cè)尾狀核的磁化率值呈負(fù)相關(guān)(r=-0.447,P=0.009)(表4)。多元線性回歸分析發(fā)現(xiàn),Apgar評(píng)分和血清總膽紅素濃度同時(shí)影響NHB組右側(cè)尾狀核的磁化率值(表5)。
2.4" 磁化率值的預(yù)測(cè)效能
ROC曲線分析顯示,殼核磁化率值預(yù)測(cè)NHB的AUC為0.780,敏感度為0.636,特異度為0.286;蒼白球磁化率值的AUC為0.692,敏感度為0.818,特異度為0.571;尾狀核磁化率值的AUC為0.619,敏感度為0.788,特異度為0.571(圖2)。DeLong檢驗(yàn)顯示,3個(gè)腦區(qū)磁化率值的AUC差異無(wú)統(tǒng)計(jì)學(xué)意義(Pgt;0.05)。
3" 討論
膽紅素神經(jīng)毒性具有區(qū)域選擇性,僅影響大腦特定區(qū)域和該區(qū)域的特定神經(jīng)元,如基底節(jié)區(qū)的少突膠質(zhì)細(xì)胞[8]。本研究首次使用QSM技術(shù)探索足月NHB患兒和足月健康新生兒深部灰質(zhì)核團(tuán)磁化率,且入組受試者常規(guī)MRI未見明顯異常信號(hào)。NHB患兒殼核磁化率值高于對(duì)照組,殼核磁化率值的升高是NHB患兒潛在腦損傷的影像依據(jù),推測(cè)其可作為腦損傷影像學(xué)標(biāo)志物,且磁化率值的變化可能先于T1WI反映的腦組織結(jié)構(gòu)變化。
NHB早期難以通過(guò)常規(guī)MRI檢測(cè)到輕微的變化,有學(xué)者認(rèn)為低頻波動(dòng)幅度可能是一種早期生物學(xué)標(biāo)志物,可為預(yù)測(cè)NHB患兒的長(zhǎng)期預(yù)后提供有價(jià)值的信息[9-10]。但長(zhǎng)時(shí)間掃描(gt;25 min)不適于新生兒。QSM技術(shù)能快速通過(guò)磁化率值的變化反映腦鐵含量的變化[11]。本研究發(fā)現(xiàn),NHB組患兒腦深部灰質(zhì)核團(tuán)鐵含量較對(duì)照組高,以殼核最顯著,推測(cè)腦深部灰質(zhì)核團(tuán)鐵含量的改變可能是NHB患者腦損傷的早期表現(xiàn)。該推測(cè)與NHB患者和動(dòng)物模型的組織學(xué)實(shí)驗(yàn)結(jié)論相吻合,即膽紅素濃度輕度升高時(shí)已有神經(jīng)毒性,即使低于臨床治療指南的標(biāo)準(zhǔn),仍可造成穩(wěn)態(tài)失衡、炎癥反應(yīng)及線粒體、質(zhì)膜的損傷等,導(dǎo)致能量代謝受損和細(xì)胞凋亡[12]。小膠質(zhì)細(xì)胞受到刺激被激活并釋放大量炎癥因子,引起神經(jīng)炎癥,進(jìn)而導(dǎo)致腦鐵含量增加[8]。因此,推測(cè)及早發(fā)現(xiàn)腦深部灰質(zhì)核團(tuán)的鐵含量異常有望成為NHB患兒腦損傷防治的重要契機(jī)。
本研究發(fā)現(xiàn),對(duì)照組蒼白球磁化率值與血清膽紅素濃度呈顯著正相關(guān),NHB組右側(cè)尾狀核的磁化率值與血清膽紅素濃度呈顯著負(fù)相關(guān),推測(cè)NHB患兒腦深部灰質(zhì)核團(tuán)鐵含量的穩(wěn)態(tài)會(huì)隨疾病的進(jìn)展而失衡。準(zhǔn)確監(jiān)測(cè)并及時(shí)維持該部位腦鐵含量的動(dòng)態(tài)平衡可能是治療腦損傷的潛在手段。經(jīng)多元線性回歸分析發(fā)現(xiàn),右側(cè)尾狀核的磁化率值亦受血清膽紅素濃度和Apgar評(píng)分的影響,提示臨床在降低NHB患兒血清膽紅素的同時(shí),要關(guān)注Apgar評(píng)分,為NHB患兒腦損傷的治療提供新思路。有學(xué)者認(rèn)為,新生兒從出生到出院應(yīng)每12 h檢測(cè)1次膽紅素水平,以減少NHB的漏診率[13]。本研究發(fā)現(xiàn),QSM技術(shù)獲取的殼核磁化率值能及時(shí)發(fā)現(xiàn)膽紅素神經(jīng)毒性易損特異性腦區(qū)鐵含量的異常,避免NHB患兒進(jìn)展為膽紅素腦病。QSM技術(shù)無(wú)創(chuàng)、快速,能直觀反映患者腦損傷情況,為臨床診療提供有力依據(jù)。
本研究的局限性:①僅針對(duì)性提取了腦深部灰質(zhì)核團(tuán)的磁化率值,后續(xù)將進(jìn)一步擴(kuò)大腦區(qū)范圍;②未跟蹤NHB患兒治療后腦鐵含量變化的情況,目前正在對(duì)受試者進(jìn)行隨訪研究;③樣本量較小,后續(xù)研究應(yīng)進(jìn)一步擴(kuò)大規(guī)模以印證結(jié)果的準(zhǔn)確性。
綜上所述,QSM技術(shù)能無(wú)創(chuàng)、靈敏、高效地反映NHB患者潛在的腦損傷,為該病的防治提供新思路和干預(yù)靶點(diǎn)。
[參考文獻(xiàn)]
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(收稿日期" 2024-04-18)